Age is Just a Number: Application of Telomere-Targeting Therapy in Combating Age-Related Diseases

Image author: Qimono (https://pixabay.com/illustrations/dna-helix-string-biology-3d-1811955/)

Written by Alex Huynh and Mahnoor Shahab

Abstract 

Given that proliferating cells often experience loss of genetic information at the ends of chromosomes due to incomplete replication in each division cycle, protective factors known as telomeres can be found at the DNA termini. Even then, these DNA-protein complexes are finite and tend to shorten over time leading to age-associated diseases or telomeropathies. Current aging populations further fuel research and scientific discoveries into several potential therapeutic strategies to treat these diseases by elongating telomeres and reducing attrition. The primary objective of this review is to provide a general overview of the current research on telomere-targeted therapies as well as to assess the potential limitations ahead. As strategies undergo human clinical trials for safety and efficacy screening, any further development in telomere-targeted therapies for anti-aging purposes needs to assess the risk of adverse side effects, oncogenesis, and various ethical concerns. 

Introduction 

Through progressive improvements in healthcare, the lifespan of the average human has been steadily increasing, but an ever-aging population raises greater concerns surrounding age-related diseases.1 The primary molecular etiology of aging diseases is declining genomic stability as a result of chromosomal attrition at the telomeric ends. During normal semi-conservative replication, DNA polymerases create a copy of the parental template with the aid of a primer. However, this process cannot accommodate the end termini of the chromosomes causing incomplete replication. Attrition over time would lead to cellular senescence as cells lose function or become unable to replicate. The main function of telomeres is to prevent this by protecting the internal regions of chromosomes from being worn away with each DNA replication. 

Telomeres are DNA-protein complexes present at the ends of linear, eukaryotic chromosomes.2 Telomeres are characterized with TTAGGG repeat and an overhang on the 3’ guanine-rich strand which folds back through the double-stranded regions creating two loops: the telomeric-loop (T-loop) and the displacement-loop (D-loop).1 Shelterin proteins will form complexes at telomeric sites to help maintain genomic stability by regulating telomere lengths and protecting chromosome ends from uncontrolled nucleolytic activity (see Figure 1).2 

FIGURE 1: Structure of a telomere.

Following the subtelomeric regions at the termini of a chromosome, the telomere comprise tandem TTAGGG repeats. Six proteins make up the shelterin complex: TRF1, TRF2, TIN2, POT1, TPP1 and RAP1. This complex helps the guanine-rich overhang invade the double stranded region to form the D-loop and T-loop structure.3 

Incomplete replication shortens the telomere ends rather than the key genomic information.2 Telomeres are regenerated through the action of telomerase, an enzyme composed of a reverse transcriptase subunit (TERT) and an RNA component (Terc) which is used as a template for telomere extension.1 However, there is insufficient telomerase expression in adult stem cells to counteract telomere attrition over time. Therefore, telomeres tend to progressively shorten with age which impairs the regenerative capacity of tissues, leading to the development of age-associated diseases. Telomere attrition can also occur prematurely due to mutations in telomere maintenance genes, leading to syndromes known as telomeropathies. The mutation gets genetically passed on and phenotypes become more severe with increasing generations.1In humans, some of the most common telomeropathies are aplastic anemia, Hoyeraal-Hreidarsson syndrome, liver disease, pulmonary fibrosis, and dyskeratosis congenita.1 These diseases display a wide range of clinical symptoms but are all categorized by the presence of critically short telomeres. 

Telomere-Targeting Therapies 

Clinically, the only approved intervention in the treatment of telomere-associated diseases is organ transplantation, which although improves the patients pertinent physical condition, does not address other organ abnormalities due to telomere attrition.1 As such, many telomere-targeting therapies demonstrate commercial and clinical interest. Research is being conducted on several therapeutic strategies which aim to modulate telomere length and cell regeneration by acting upon telomeric factors mentioned above. By promoting telomere maintenance, these therapies may be a promising strategy to restore the regenerative properties of tissues and prevent age-related diseases. 

Chemical Activator Therapy 

The use of telomerase activators is a potential strategy for the treatment of age-associated illnesses. The most widely studied chemical activator is TA-65, derived from Astragalus membranaceus extract.1 This molecule has been shown to increase average telomere length and elongate critically short telomeres in adult mice cells.4 However, it had no effect in telomerase-deficient mice, indicating that the mechanism of TA-65 is dependent on the telomerase pathway.4 Dietary supplementation of TA-65 was further used to study the in vivo telomere dynamics in mice.4 The results showed a 10-fold increase in TERT expression but average telomere length had not significantly increased.4 However, there was a significant decrease in the amount of short telomeres, indicating that TA-65 promotes rescue of critically short telomeres.4 A similar result was seen in studies assessing the role of TA-65 in humans, in which there was a minimal impact on mean telomere length but the percentage of critically short telomeres decreased significantly.4 Additionally, the presence of TA-65 in mice diets improved their capacity to uptake glucose and decreased blood insulin levels.4 Since glucose intolerance and insulin resistance are primary indicators of aging in mice, it can be concluded that continued intake of TA-65 can contribute to improvements in health span.4 However, the balance between health enhancement and lifespan does not always correlate. The impacts of TA-65 on longevity are still being researched and existing studies have shown contradictory results. Nonetheless, a notable benefit of using a telomerase activator such as TA-65 is that it is non-invasive; the molecule is derived from an herb and can easily be orally administered. There are currently no known side effects other than the possibility of increased cancer risk, but long-term safety studies are needed to further determine the impact of TA-65.5 Thus, telomerase activators have great therapeutic potential and are worth looking into for future research. 

Hormone Therapy 

Alternatively, hormones have been shown to stimulate TERT expression which indicates a potential application of hormonal therapies in the treatment of age-associated diseases.1,6 Historically, androgen therapy has been shown to increase the survival of patients with aplastic anemia, a common telomeropathy characterized by insufficient hemopoietic cells in the bone marrow and peripheral pancytopenia.1,6 Calado et al. (2009) demonstrated that the sex hormone’s exposure to peripheral blood lymphocytes and CD34+ T lymphocyte increases telomerase activity that coincides with increased TERT mRNA expression. 6 Specifically, androgens are thought to undergo intracellular conversion into estradiol or are metabolized into estrogen-associated metabolites.6 Estradiol, in turn, complexes with estrogen receptors that dimerize and bind to estrogen response elements on the TERT promoter region, thereby upregulating the production of TERT.6 One prospective phase I/II clinical trial using androgen therapy found that 11 of the 12 evaluable patients showed reduction of telomere attrition and most also showed significant hematological improvement at a two year follow up, suggesting that hormone therapy has the potential to attenuate age-related diseases.7 However, ten patients were removed from the study due to varying adverse events such as dangerous increases in liver enzymes or edema.7 With potent effects, more research is needed to investigate new synthetic alternatives for application in hormonal therapy with fewer side-effects and limitations common to steroids such as dependence development or increasing tolerance.6 

Gene Therapy 

The most promising avenue of telomere research is gene therapy which seeks to transfer genes essential for telomere maintenance such as using a human-TERT expressing adeno-associated viruses (AAVs) to transiently activate telomerase.1 A study using AAV9 vectors in mice was able to re-activate telomerase activity in a wide range of tissues which ultimately had beneficial effects on mouse health, such as delayed osteoporosis and improved neuromuscular coordination.8In particular, AAV9-TERT treatment in elderly mice reactivated telomerase in their lungs.8 This may be a potential therapeutic strategy for treatment of pulmonary fibrosis, as this disease is often associated with short telomeres due to mutations in telomerase.8 The feasibility of this gene therapy requires further investigation and research before it can be implemented in a clinical setting. Furthermore, telomerase gene therapy can also serve to be a potential treatment for cardiovascular diseases. AAV-TERT treatment on cardiac tissue in mice showed improved heart function upon myocardial infarction.1 Compared to the previous exogenous telomerase stimulating strategies, telomerase gene therapy is applicable to a wider range of patients such as those with pre-existing mutations in telomere maintenance genes.1 Despite the beneficial health effects, telomerase activation strategies need to be taken with caution since cells with hyper-long telomeres may become cancerous. Nevertheless, TERT gene therapy still remains a promising candidate for the treatment of human telomeropathies and is worthy of further investigation. 

Limitations & Future Directions 

Telomere-targeting therapies offer many potential applications in preventing cellular senescence and telomeropathies. However, excessive telomerase activation has also been shown to cause adverse effects.9 Although premature or aberrant cellular senescence causes many diseases, disruption to the process may enable indefinite, uncontrolled proliferation of cells causing oncogenesis.9 Upregulation of telomerase activity or activation of alternative pathways for telomere lengthening may allow premalignant cells to achieve immortalization (unlimited divisions) and progress onto a more cancerous stage.1,9 Thus, application of telomere gene therapy to combat age-associated diseases needs to address oncogenesis safety concerns. 

Although extensive research has been conducted on telomere gene therapies, there is still a long way to go before the knowledge can be translated to a clinical setting. The majority of the research has been done with mouse models and currently, some telomere-therapies have moved on to the clinical trials phase. However, the path is still long as there are many factors that need to be considered. It is particularly challenging due to the fact that telomerase activity can have opposing effects on aging and cancer incidence (see Figure 2).1 Thus, developing telomere-based anti-aging and anti-cancer therapies is a very intricate and complex process. Telomere gene therapy remains a promising therapeutic strategy for treatment of malignancies and age-associated diseases. However, additional studies on clinical applications and long-term effects on human health are needed. 

FIGURE 2: Telomerase has physiologically antagonistic effects in cancer and aging, such that a deficiency in telomerase leads to short telomeres which results in aging. Conversely, increased telomerase activity may lead to tumorigenesis.10 

The possibility of using telomere-based therapies to alter the mechanisms of aging and extend the human lifespan beyond the norm has raised many ethical concerns, such as impact on mental health. Psychological connectedness weakens over time and a prolonged extension of biological life might damage one’s personal identity.11 An extended lifespan may also create problems for the human population due to increased competition for limited resources, decreasing overall quality of life.11 Moreover, there is religious controversy associated with anti-aging and gene therapies. Several groups believe that aging and death is a natural phenomenon. They are of the opinion that it is not necessarily a ‘problem’ that needs to be fixed and attempting to reverse aging or genetic mutations would be going against God’s vision for the world.11 Therefore, telomere-based therapies in relation to combating aging have many ethical issues associated with them and different perspectives that need to be taken into consideration. 

Conclusion 

The application of telomerase-based therapies as a treatment for telomeropathies and age-associated illnesses is a rapidly growing topic of interest to many researchers. Chemical activators such as the plant-based molecule TA-65 can be used to activate telomerase. Studies using mouse models show that TA-65 can enhance health span but it’s role in longevity remains unknown. Additionally, the production of TERT can be upregulated with androgen therapy. In clinical trials, this method has shown a reduction of telomere attrition and can also be used to enhance survival in aplastic anemia patients. However, telomerase gene therapy remains the most promising candidate for treatment of telomeropathy due to its ability to directly activate telomerase. The beneficial health effects shown in mouse models highlights the therapeutic potential of this method but several key challenges must be addressed before implementation in a clinical setting. Adverse side effects, oncogenic risk and ethical concerns are among the larger barriers in need of further investigation. Nevertheless, telomere-targeting therapies offer a therapeutic strategy to combat the underlying cause of many age-related diseases beyond the surface symptoms. 

References 

1. Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017;216(4): 875–87. Available from: doi:10.1083/jcb.201610111. 2. Chan SRWL, Blackburn EH. Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci. 2004;359(1441): 109–21. 

3. Maestroni L, Matmati S, Coulon S. Solving the telomere replication problem. Genes. Multidisciplinary Digital Publishing Institute; 2017;8(2): 55. Available from: doi:10.3390/genes8020055. 

4. de Jesus BB, Schneeberger K, Vera E, Tejera A, Harley CB, Blasco MA. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging cell. 2011;10(4): 604–21. Available from: doi:10.1111/j.1474-9726.2011.00700.x. 

5. Tsoukalas D, Fragkiadaki P, Docea AO, Alegakis AK, Sarandi E, Thanasoula M, et al. Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives. Mol Med Rep. 2019;20(4): 3701–8. Available from: doi:10.3892/mmr.2019.10614. 

6. Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114(11): 2236–43. Available from: doi:10.1182/blood-2008-09-178871. 

7. Townsley DM, Dumitriu B, Liu D, Biancotto A, Weinstein B, Chen C, et al. Danazol treatment for telomere diseases. N Engl J Med. 2016;374(20): 1922–31. Available from: doi:10.1056/NEJMoa1515319. 

8. Bernardes de Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012;4(8): 691–704. Available from: doi:10.1002/emmm.20120024. 

9. Hong J, Yun C-O. Telomere gene therapy: Polarizing therapeutic goals for treatment of various diseases. Cells. 2019;8(5). Available from: doi:10.3390/cells8050392. 10. Ozturk MB, Li Y, Tergaonkar V. Current insights to regulation and role of telomerase in human diseases. Antioxidants. Multidisciplinary Digital Publishing Institute; 2017;6(1): 17. Available from: doi:10.3390/antiox6010017. 

11. Glannon W. Identity, prudential concern, and extended lives. Bioethics. 2002;16(3): 266–83. Available from: doi:10.1111/1467-8519.00285. 

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